Amino-acylamino-acylamino-penicillanic acids



3,268,514 AMINO-ACYLAMINO-ACYLAMINO- PENICTLLANHC ACIDS Norman H. Grant, Wynnewood, and Harvey E. Aiburn,

West Chester, Pa, assignors to American Home Products Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Apr. 7, 1964, Ser. No. 358,049 14 Claims. (Cl. 260-2391) where X X X and X are of the group consisting of hydrogen, alkyl, hydroxy, alkoxy, halo, amino and nitro; and

Y is of the group consisting of:

Where R is of the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkaryl, and substituted alkaryl; and

R is of the group consisting of alkyl and aryl;

NHz

where 21:2 to 9;

where R R R and R are of the group consisting of hydrogen, alkyl, nitro, sulfo, amino, halo and hydroxy;

R and R R and R and R and R when respectively joined, complete a ring of the group consisting of aryl and alicyclic; and

R is of the group consisting of hydrogen and lower alkyl;

United States Patent 0 "ice where R R R and R are of the group consisting of hydrogen, alkyl, hydroxy, alkoxy, halo, amino and nitro;

( RS-(CHz)nCI3HOO- where 11:1 to 5, and R is the group consisting of (a) hydrogen, alkyl, and

in which case A is a second residue of the penicillanic acid derivative of Formula I above, and n'=1 to 5;

where R is of the group consisting of hydroxy and alkyl, and 11:2 to 7; and

where 11:1 to 4.

The new compounds of the series defined above show desirable broad spectrum antibacterial activity and are useful as therapeutic agents in poultry and mammals, including man, in'the treatment of infectious diseases caused by Gram-positive and Gram-negative bacteria, upon either parenteral or oral administration.

The general process for preparing the aforesaid novel amino-acylamino-acylamino-penicillanic acids is described and claimed in said copending application and comprises generally the reaction of a 4-substituted-2,5-oxazolidinedione (also known as an N-carboxy-amino acid anhydride) with a 6-(amino-acylamino)penicillanic acid under controlled conditions. Methods for the preparation of the N-carboxy amino acid anhydride and 6-(aminoacylamino)penicillanic acid reactants suitable for use in the process are also described in or referred to in said copending application.

In a preferred method for preparing the amino-acylamino-acylamino-penicillanic acids of the present invention, the 4-substituted-2,5-oxazolidinedione chosen is reacted with the selected 6-(a-amino-acylamino)penicillanic acid in approximately equimolar quantities in a cold aqueous solution in a pH range from about 3.8 to about 7.4 and preferably in the range 4.7-7.0. The mixture is stirred for several hours at a temperature from just above the freezing point of the aqueous mixture to about 37 C., and preferably in the range 010 C. Although not essential, it may be preferred to include a buffer having an ionic strength of about 0.02, preferably about 0.3, to aid in keeping the reaction mixture within the required pH range. Suitable buffers for maintaining the desired pH may be any mixture of organic or inorganic watersoluble acids, bases, or salts such as sodium acetate-acetic acid, calcium acetate-acetic acid, pyridine-acetic acid, formic acid-ammonia, etc. Alternatively, the reaction mixture may be maintained within the requisite pH range by careful addition of a base such as NaOH or the like.

The following examples are illustrative of the invention, but are not to be considered necessarily limitative thereof.

EXAMPLE I 6-[L-a-(D-Z-amino-Z-phenylacetamido)ind0le-3-pr0pi0namido1penicillanic acid Mix 482 mg. (1.2 millimoles) of G-(L-a-aminO-fidndole-3-propionamido)penicillanic acid with 212 mg. (1.2

millimoles) of D-phenylglycine-N-carboxyanhydride in 3 30 ml. of ice-cold water. Stir at 1-2 for 60 minutes, keeping the pH at 6.0 by the addition of 1 N NaOH. Filter, and freeze-dry the filtrate. The product is active against Staph. aureus and E. coli.

EXAMPLE II 6- [D-a- (Z-aminoacetamido) indle-3-propi0namido] penicillanic acid Mix 161 mg. (0.4 millimole) of 6-(D-a-aminoindole- 3-propi0namido)penicil-lanic acid with 40 mg. (0.4 millimole) of the N-carboxyanhydride of glycine in 10 ml. of ice-cold water. Stir at 12 for 60 minutes, keeping the pH at 6.0 by the addition of 1 N NaOH. Filter, and freeze-dry the filtrate. The product is active against both Staph. aureus and E. coli.

EXAMPLE III When in the procedure of Example II, the N-carboxyanhydride of glycine is replaced by 0.4 millimole of the N-carboxyanhydride of (1) D-leucine (2) D-phenylglycine (3) D-phenylalanine (4) L-phenylalanine (5) 1-aminocyclobutanecarboxylic acid (6) 1-aminocyclopentanecarboxylic acid (7) anthranilic acid (8) Z-amino-S-nitrobenzoic acid (9) D-tryptophan (10) L-tryptophan (11) D-methionine (12) DL-phenylsarcosine (13) N-phenylglycine (14) o-ethoxy-DL-phenylglycine (15) L-cystine (16) Z-amino-S-chlorobenzoic acid (17) 2-amino-5-methylbenzoic acid respectively, the following corresponding penicillin derivatives, all active against Gram-positive and Gram-negative microorganisms, are produced:

(1) 6 [D-a-(D-2-amino-4-methylvaleramido)indole-3- propionamido1penicillanic acid (2) 6 [D u (D-2-amino-2-phenylacetamido)indole-3- propionamido]penicillanic acid (3) 6 [D-a-(D-2-amino-3-phenylpropionamido)indole- 3-propionamido]penicillanic acid (4) 6 [D-a-(L-2-amino-3-pheny1propionamido)indole- 3-propionamido]penicillanic acid (5) 6 [D-a-(1-aminocyclobutanecarboxamido)indole-3- propionamido]penicillanic acid (6) 6 [D-ot-(1-aminocyclopentanecarboxamido)indole- 3-propionamido]penicillanic acid 7) 6 [D a-(Z-aminobenzamido)indole-3-propionamido] penicillanic acid (8) 6 [D-a-(2-amino-5-nitrobenzamido)ind0le-3-propionamido]penicillanic acid (9) 6 [D-a-(D-a-aminoindole-3-propionamido)indole- 3-propionamido]penicillanic acid 10) 6 [D-a-(L-a-aminoindole-3-propionamido)indole- 3-propionamido]penicillanic acid (11) 6 [D a-(D-Z-amino-4-methylthiobutyramido)indole-3-propionamidoJpenicillanic acid (12) 6 [D a-(DL-Z-methylamino-Z-phenylacetamido) indole-3-propionamido]penicillanic acid (13) 6 [D-a-(2-anilinoacetamido)indo1e-3-propionamido] penicil'lanic acid (14) 6 [D-a-(DL-Z-amino-2-o-ethoxyphenylacetamido) indole-3-propionamido]penicillanic acid 15) bis[6 (D 0c L-3-thio-2-aminopropionamido)indole-3-propionamido)penicillanic acid (16) 6 [D-a-(2-amino-5-chlorobenzamido)indole-3-propionamid0]penicillanic acid Cit 4 17) 6 [D u-(2-amino-S-methylbenaamido)indole-3- propionamido] penicillanic acid EXAMPLE IV When in the procedure of Example I, the N-carboxyanhydride of D-phenylglycine is replaced by 1.2 millimoles of the N-carboxyanhydride of the corresponding penicillin derivatives, all active against Gram-positive and Gram-negative microorganisms, are produced.

EXAMPLE V When in the procedure of Example I, the 6-(L-u-aminofi-indole-3-propionamido)penicillanic acid is replaced by 1.2 millimoles of 6-(L-a-amino-5-methylindole-3-propion-.

amido)penicillanic acid, the corresponding penicillin product, active against both Staph. aureus and E. coli, is produced.

EXAMPLE VI When in the procedure of Example I, the 6-(L-a-aminofl-indole-3-propionamido)penicillanic acid is replaced by 1.2 millimoles of 6-(L-u-amino-5-ethyl-indole-3-propionamido)penicillanic acid, the corresponding penicillin product, active against both Staph. aureus and E. coli, is produced.

EXAMPLE VII When in the procedure of Example I, the G-(L-a-amino- B-indole-3-propionamido)penicillanic acid is replaced by 1.2 millimoles of 6-(L-u-amino-5-methoxyindole-3-propionamido)penici1lanic acid, the corresponding penicillin product, active against both Staph. aureus and E. coli, is produced.

As will be understood by those skilled in the art, the compounds of the invention may be utilized in their acid form or in the form of the therapeutically-active salts thereof, e.g., the sodium or potassium salts, or hydrochloride, etc., or in the form of the pharmaceuticallyacceptable acid-addition salts prepared by the reaction of the penicillin compounds with an amine or diamine base, e.g., procaine, or various N,N'-disubstituted alkylenediamines, such as N,N'-dibenzylethylene-diamine, etc.

We claim:

1. A compound of the formula:

8 CH; X CH:('1HCONH(l1H-Cfi o oflt NH O=CN' CCOOH X I N Y H X4 where X X X and X are of the group consisting of hydrogen, lower alkyl, and lower alkoxy; and Y is the group consisting of: (1) R (l/H-CO- wherein R is of the group consisting of hydrogen, lower alkyl, phenyl, (1ower)a1kylphenyl, (1ower)a1koxypheny=1,

(CH2)n C-C NIIQ where n=2 to 9;

11 HNR wherein R R R and R are of the group consisting of hydrogen, alkyl, sulfo, nitro and chloro; R and R when joined complete a naphthylene ring;

and R is of the group consisting of hydrogen and lower alkyl;

ra CHz(l3H-C 0- R3 NHz where R R R and R are of the group consisting of hydrogen, lower alkyl and lower alkoxy;

s,2es,5 14

6 where 11:1 to 5, and R is the group consisting of hydrogen and lower alkyl;

F (5111).. HC-C owhere R is of the group consisting of hydroxy and alkyl, n=2 to 7; and

Where 11:1 to 2.

2. 6-[L-a-(D-2-amino 2 pheny1acetamido)indole-3- propionarnido1penicillanic acid.

3. 6 [D a (2 aminoacetamidofindole 3 propionamido1penicillanic acid.

4. 6 [D or. D (2 amino 4 methylvaleramido) indole 3 propionarnidolpenicillanic acid.

5. 6 [D a (D 2 phenylacetamido)indole 3 propionarnido]penicillanic acid.

6. 6 [D oz (D 2 amino 3 phenylpropionamido) indtol e-3-propionarnido]penicillanic acid.

7. 6 [D a (L 2 amino 3 phenylpropionamido) indole 3 propionamidolpenicillanic acid.

8. 6 [D a (l aminocyclobutanecarboxamido)indole 3 propionarnido]penicillanic acid.

9. 6 [D lX (1 aminocyclopentanecarboxamido) indole 3 propionarnido]penicil1anic acid.

10. 6 [D a (o-arninobenzamido)indole 3 propionamido1penici1lanic acid.

11. 6 [D a (2 amino 5 nitrobenzamido)indole- 3 propionamido1penicillanic acid.

12. 6 [D a (D oz aminoindole-3-propionamido) indole 3 propionamido]penicillanic acid.

13. 6 [D a (DL 2 methylarnino 2 phenylacetamido)indole 3 propionamido1penicil1anic acid.

14. 6 [D a (2 anilinoacetarnido)indole 3 propionamidoJpenicillanic acid.

No references cited.

ALEX MAZEL, Primary Examiner.

HENRY R. J ILES, Examiner.

JAMES W. ADAMS, JR., Assistant Examiner. 

1. A COMPOUND OF THE FORMULA: 